Apolipoprotein epsilon 4 allele modifies waist-to-hip ratio effects on cognition and brain structure.

Background: This study aimed to determine whether relationships between obesity, as measured by waist-to-hip ratio (WHR), and cognition and brain structure were modified by the apolipoprotein epsilon 4 allele (apoE4).

Methods: The sample included 1969 stroke- and dementia-free participants from the Framingham Offspring Cohort who underwent neuropsychological (NP) testing and structural magnetic resonance imaging (MRI) between 1999 and 2002. WHR was categorized into sex-specific quartiles with those in Q4 representing central obesity. Multivariate linear regression estimated the relationships between Q4-WHR, cognitive, and MRI measures; interaction terms examined modification of these relationships by the presence of apoE4. All analyses were cross sectional.

Results: ApoE4 status significantly modified a number of associations. Specifically, we observed a significant negative relationship between Q4-WHR and a measure of executive function in the apoE4(+) group but not in the apoE4(-) group. Similarly, we observed a stronger negative relationship between Q4-WHR and a measure of memory function for those in the apoE4(+) group compared to those in the apoE4(-) group. In addition, apoE4 status modified the relationship between Q4-WHR and 2 measures of structural brain integrity. First, a paradoxical finding of a negative association between WHR and frontal brain volume that was significant only for those in the apoE4(-) group, and a second finding that WHR was significantly associated with greater white matter hyperintensity volume only in the apoE4(+) group.

Conclusions: These findings suggest that associations between central adiposity and both neuropsychological performance and underlying brain structure are highly complex and must be considered in the context of possible modifying genetic influences.